Effect of tracheotomy timing on patients receiving mechanical ventilation: A meta-analysis of randomized controlled trials

Purpose We assessed the effects of tracheostomy timing (early vs. late) on outcomes among adult patients receiving mechanical ventilation. Methods PubMed, Embase, Web of Science and Cochrane Library were searched to identify relevant RCTs of tracheotomy timing on patients receiving mechanical ventilation. Two reviewers independently screened the literature, extracted data. Outcomes in patients with early tracheostomy and late tracheostomy groups were compared and analyzed. Meta-analysis was performed using Stata14.0 and RevMan 5.4 software. This study is registered with PROSPERO (CRD42022360319). Results Twenty-one RCTs were included in this Meta-analysis. The Meta-analysis indicated that early tracheotomy could significantly shorten the duration of mechanical ventilation (MD: -2.77; 95% CI -5.10~ -0.44; P = 0.02) and the length of ICU stay (MD: -6.36; 95% CI -9.84~ -2.88; P = 0.0003), but it did not significantly alter the all-cause mortality (RR 0.86; 95% CI 0.73~1.00; P = 0.06), the incidence of pneumonia (RR 0.86; 95% CI 0.74~1.01; P = 0.06), and length of hospital stay (MD: -3.24; 95% CI -7.99~ 1.52; P = 0.18). Conclusion In patients requiring mechanical ventilation, the tracheostomy performed at an earlier stage may shorten the duration of mechanical ventilation and the length of ICU stay but cannot significantly decrease the all-cause mortality and incidence of pneumonia.


Introduction
Many patients are admitted to the intensive care units (ICU) each year because they require mechanical ventilation [1].Mechanical ventilation (MV) is usually performed through orotracheal intubation (OTI) or a tracheostomy tube.Tracheostomy is often considered when a patient requires prolonged mechanical ventilation or improved respiratory status [2].Tracheostomy is one of the routine procedures for the critical care population.Tracheotomy can have a positive impact on the improvement of the patient's respiratory function compared to continuous translaryngeal endotracheal intubation.Tracheotomy reduces injuries to the larynx and upper airway from endotracheal tube, facilitates the removal of secretions, increases the mobility of patients, reduces the need for sedation, and enhances the comfort of patients [2][3][4][5].However, as an invasive operation, tracheotomy may lead to complications such as tracheal stenosis, incisional infection, hemorrhage, and fistula formation [6][7][8].
In recent years, many studies have explored the optimal timing of tracheotomy.However, the conclusions of many relevant studies are inconsistent [9][10][11][12][13][14].Similarly, previous metaanalysis assessing the effects of early and late tracheotomy on patients undergoing mechanical ventilation have yielded different clinical outcomes [15][16][17][18][19].The optimal timing of tracheotomy is a controversial subject and that is worth continuing to explore.Therefore, we performed this updated meta-analysis to determine the effect of tracheostomy timing on patients undergoing mechanical ventilation.

Search methods
Two investigators independently and systematically searched PubMed, Embase, Web of Science and Cochrane Library to identify RCTs about the early and late tracheotomy published up to September 2022.We used a combination of medical subject headings (MeSH) and keyword terms to search.The search terms included mechanical ventilation, ventilator, intratracheal intubation, tracheostomy, and tracheotomy.The search was limited to published articles.In addition, references mentioned in the identified articles were manually searched to identify additional studies that might be eligible.

Selection criteria
The inclusion criteria: (1) Population: patients requiring mechanical ventilation in critical care units; (2) Intervention: early tracheotomy; (3): control: late tracheotomy; (4) outcomes: mortality, the incidence of pneumonia, mechanical ventilation days or ventilator-free days, length of hospital stay, length of stay in ICU.At least one outcome was reported.(5) study design: randomized controlled study.

Data collection and study quality assessment
Two investigators independently screened studies based on the criteria, retrieved potentially relevant studies, extracted study data, and evaluated the quality of the eligible studies.Information extracted from these studies included the first authors, name, publication year, country, setting, sample size, patient characteristics (age, sex ratio, disease severity), inclusion and exclusion criteria, the timing of early and late tracheotomy, and major outcomes.Different studies have defined the timing of early and late tracheotomy differently.The primary outcome was mortality and incidence of ventilator-associated pneumonia.The secondary outcomes included duration of mechanical ventilation, length of ICU stay and length of hospital stay.The quality evaluation of the included RCTs was evaluated using the methods recommended by the Cochrane systematic review manual for assessing risk of bias.Any disagreements between the investigators were resolved by third investigators reviewing the original study or consulting the corresponding author.

Statistical analysis
Continuous data were presented as mean differences (MDs) and 95% confidence intervals, whereas binary data were presented as Relative risk (RRs) and 95% confidence intervals.Heterogeneity of included studies was tested by chi-square test and quantitatively assessed using the I 2 value.I 2 < 50.0% or P > 0.1 was considered as no significant heterogeneity.If the heterogeneity between studies was not significant (p � 0.1, I 2 � 50%), the fixed effects model was used for analysis.If there was significant heterogeneity among the included studies (p < 0.1, I 2 > 50%), the random effects model was used for analysis.Publication bias was evaluated using the funnel plots.Subgroup analysis of mortality and ventilator-associated pneumonia was performed according to different study characteristics.These data were analyzed using RevMan 5.4 system software and Stata 14.0 software.The robustness of the pooled results was assessed by sequentially excluding individual studies.Significance is defined as 2-sided P <0.05.

Eligible literature search results and study characteristics
We manually searched the references from similar studies and identified a new eligible study [28].A total of 1573 potential articles were identified based on our search strategy.409 articles were excluded due to duplication.Eventually, 21 RCTs [5,10,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] involving 3621 patients were enrolled for this meta-analysis.The flow diagram of the literature search and study selection is shown in Fig 1 .There were 1796 in the early tracheotomy group and 1825 in the late tracheotomy group.Included patients had different indications for intubation, and the definitions of early and late tracheotomy varied in the trials.The baseline information of the eligible studies is shown in Tables 1 and 2.

Risk of bias of enrolled trials
The quality evaluation revealed that the overall risk of bias of included trials was deemed to have low or unclear.Due to the characteristics of the intervention nature of tracheotomy, it was difficulty to blind clinicians and patients.However, objective outcomes, such as mortality, and incidence of ventilator-associated pneumonia, are unlikely to be affected by the absence of blinding.The quality evaluation is shown in Fig 2.

Main results
Mortality.Twenty studies [5,10,[20][21][22][23][24][25][26][27][29][30][31][32][33][34][35][36][37][38] have reported mortality data with different timing of tracheotomy.The overall mortality in the early tracheotomy group was 25.03%, and in the late tracheotomy group was 28.34%.Because of the heterogeneity among the included studies was not significant (p = 0.06; I 2 = 37%; Fig 3), the fixed model was used for the analysis.The analysis showed no significant difference in mortality between the early and late tracheotomy groups (RR 0.86; 95% CI 0.73-1.00;p = 0.06; Fig 3).There was no significant publication bias in funnel plots (Fig 4).The sensitivity analysis showed that this conclusion was not robust, and altered especially when the Bosel et al. study [37] was excluded (Fig 5).In addition, we performed subgroup analysis according to the different characteristics of the study.The subgroup analyses showed that early tracheotomy might have beneficial effects on the risk of mortality (mean age of patients �60.0 years, patients used percutaneous tracheotomy) (Table 3).The interaction P test showed that age (P = 0.03) might influence the treatment effect of tracheotomy timing on the mortality risk.
Incidence of ventilator-associated pneumonia.Eighteen studies [5, 20-30, 32-36, 38] reported data on the incidence of pneumonia.Pneumonia is a common clinical complication in mechanically ventilated patients.The overall incidence of pneumonia in the early tracheotomy group was 31.46%, and in the late tracheotomy group was 37.91%.There was significant heterogeneity among the included studies (I 2 = 71%; P< 0.0001; Fig 6), so the randomized model was used for analysis.Although the incidence of pneumonia was lower in patients who underwent early tracheotomy, the difference was not statistically significant (RR: 0.86; 95% CI: 0.74-1.01;P = 0.06; Fig 6).There was no significant publication bias in funnel plots (Fig 7).The sensitivity analysis showed that this conclusion was stable and not changed by excluding any particular studies (Fig 8).The results of subgroup analysis showed that early tracheotomy was associated with a reduced risk of ventilator-associated pneumonia if the trial sample size was �100 (Table 4).

Discussion
This updated meta-analysis evaluated the effect of tracheotomy timing on patients receiving mechanical ventilation.This study included a total of 21 randomized controlled trials (RCTs) involving 3621 patients.The included studies described in detail the inclusion and exclusion criteria for the observed population.In addition, most of the studies also comprehensively described the baseline data of the patients.The pooled analysis of this study showed that early tracheotomy reduced the duration of mechanical ventilation and length of ICU stay.Mortality and incidence of pneumonia were lower in the early tracheotomy group compared with the late tracheotomy group, but this was not statistically significantly different.In addition, we conducted subgroup analyses based on the characteristics of different studies to explore the effect of timing of tracheotomy on short-term clinical outcomes in mechanically ventilated    patients.The subgroup analysis showed that early tracheotomy may have potential clinical benefits for patients aged �60 years or who underwent percutaneous tracheotomy.The clinical outcomes of early and late tracheotomy may be influenced by the age of the patients and the methods of tracheotomy.
In the ICU, many patients require mechanical ventilation.The coronavirus disease 2019 (COVID-19) pandemic in recent years has led to a significant increase in the number of patients requiring mechanical ventilation.Many patients positive for COVID-19 require prolonged mechanical ventilation in the ICU [39].Tracheotomy is a commonly performed surgical procedure for patients who require prolonged mechanical ventilation.Nevertheless, the timing of tracheotomy in mechanically ventilated patients has been controversial.There are still no clear criteria to guide the timing of tracheotomy.A number of randomized controlled trials have explored the effects of early and late tracheotomy on mechanically ventilated patients.However, the conclusions were inconsistent.Similarly, some meta-analysis on this topic has reached inconsistent conclusions [15,17,19,40].The meta-analysis performed by    Wang et al. [17] showed that early tracheotomy did not provide significant clinical benefits to patients requiring mechanical ventilation.However, a meta-analysis conducted by Chorath et al. [19] suggested that early tracheotomy was associated with a lower incidence of ventilatorassociated pneumonia, shorter mechanical ventilation, and length of ICU stay.Novel RCTs [36][37][38] on this topic have recently been published.These studies were not included in the new meta-analysis.The inclusion of these newly published studies may address some of the questions on this topic.In addition, it should be pointed out that previous meta-analyses included many retrospective studies and did not perform stratified analyses.
To determine the impact of tracheotomy timing on patients, we included only randomized controlled trials in our meta-analysis and included newly published randomized controlled studies.We compared this study with recently published meta-analysis on this topic.Compared with the Chorath study [19], our study included seven other relevant [20,21,25,32,[36][37][38]. Compared with the study of Deng et al. [41], we included seven additional relevant RCTs [28,32,[34][35][36][37][38].As far as we know, this is probably the meta-analysis to date involving the largest number of patients, and the results are more reliable.
The pooled results of the meta-analysis showed no statistical significance in mortality between the early and late tracheotomy groups.Sensitivity analysis showed that this result was not robust, and altered especially when the Bosel et al.Study [37] was excluded.This may be due to the higher proportion of young people in the study by Bosel et al. [37].Our subgroup analysis showed that the effect of tracheotomy timing on mortality was by the age of patients.Subgroup analysis found that early tracheotomy was associated with reduced mortality for patients underwent percutaneous tracheotomy.Percutaneous dilated tracheostomy offers the same safety as surgical tracheostomy [42].Some studies [42][43][44] have shown that percutaneous tracheotomy reduces the overall incidence of inflammation and may further reduce clinically relevant hemorrhage rates and mortality.In addition, percutaneous tracheotomy does not require the involvement of the entire surgical team and the procedure takes less time.Percutaneous tracheotomy seems to be more clinically advantageous in the ICU [43,44].In the subgroup analysis of the effects of different etiologies on mortality, the 21 studies were divided into "trauma group", "neurology group" and "other disease group".However, subgroup analysis showed no reduction in mortality due to early tracheotomy in all three groups.This may be because we defined mortality as all-cause mortality in the study.Patients with tracheal intubation tend to have more complex conditions, and the complexity and severity of the disease can affect changes in all-cause mortality.
Pulmonary infections are a common complication in mechanically ventilated patients.Some studies [19] have indicated that early tracheotomy is beneficial to reduce the occurrence of ventilator-associated pneumonia.Nevertheless, this meta-analysis showed that early tracheotomy did not reduce the incidence of pneumonia.This is consistent with the results of Deng et al. [41].The results of five [21,25,32,36,38] of the six RCTs [20,21,25,32,36,38] newly included in this meta-analysis suggested that early tracheotomy was not associated with reduced incidence of pneumonia.It is not certain whether pneumonia is caused by ventilator ventilation or by other causes.It is important to note that tracheotomy itself can also lead to an increased incidence of pneumonia [45].These may have some impact on the results.The possible reason is that tracheotomy disrupts the natural structure of the airway, reducing the protective effect of the airway and the cough reflex.In the ICU, the benefits of tracheotomy can be negated by frequent invasive procedures.In the subgroup study of the effects of different diseases on the incidence of pneumonia, early tracheotomy did not reduce the incidence of pneumonia in the "trauma group", "neurology group" and "other disease group".The incidence of pneumonia is not affected by the tracheotomy itself or its timing.The subgroup analysis showed that early tracheotomy might provide clinical benefit when the sample size of trials was �100.
Meta-analysis showed that early tracheotomy was associated with shorter mechanical ventilation days and length of ICU stay.Nevertheless, there was no significant difference in the length of hospital stay between the two groups.This may be because early tracheotomy was associated with reduced airway resistance, reduced respiratory work, reduced dead space, better secretion clearance, and enabling respiratory muscles to exercise and recover [41,46].Tracheotomy improves patients' spontaneous breathing, thus reducing the duration of mechanical ventilation [47].Moreover, compared with intubation, tracheotomy is more comfortable and reduces the need for analgesic and sedative drugs.This may also help patients regain respiratory function and reduce the length of mechanical ventilation and ICU stay.Sensitivity analysis showed that the conclusion of ventilator days was not stable, especially after excluding the study of Rodriguez et al. [20].Rodriguez's study included patients with multiple injuries requiring mechanical ventilation, which specifically included younger patients.
At present, there is no uniform standard for early and late tracheotomy timing.The definitions of the timing of early and late tracheotomy are also not uniform in different studies.In most studies, tracheotomy within 7 to 10 days after endotracheal intubation is considered as early tracheotomy.Therefore, the timing of early tracheotomy was defined as within 10 days after endotracheal intubation in this study.The primary condition for determining whether a patient needs an early tracheotomy is to accurately predict which patients are likely to require long-term mechanical ventilation.It is difficult to predict something accurately.If the prediction fails, a proportion of patients who do not require early tracheotomy may be included in the early tracheotomy group, thus affecting the reliability of the study results.This may lead to the misconception that patients in the early tracheotomy group are more likely to resume spontaneous breathing and have a lower incidence of ventilator-associated pneumonia.However, we have to admit that in clinical practice, there is still a lack of simple tools to accurately predict whether a patient needs long-term mechanical ventilation.
This meta-analysis also has some limitations.First, of the 21 RCTs included, only six [5,10,21,26,28,33] were in comprehensive ICU patients, while the other studies were in specialized ICU patients.Second, there was significant heterogeneity in the included studies.The heterogeneity of this meta-analysis may be attributed to different inclusion and exclusion criteria for participants in different literature, different severity of disease in participants, different definitions of the timing of early and late tracheotomy, and different diagnostic criteria in different studies.For example, Barquist et al. [25] used the Centers for Disease Control and Prevention (CDC) diagnostic criteria for pneumonia, whereas Terragni et al. [26] used a simplified CPIS score (>6) to diagnose ventilator-associated pneumonia.Third, whether a patient requires long-term mechanical ventilation is often determined by the clinician based on the patient's clinical manifestations, which can also influence the study results to some extent.
In conclusion, early tracheotomy reduces the duration of mechanical ventilation and length of ICU stay and does not significantly reduce the incidence of pneumonia, mortality, or length of hospital stay.However, there are many factors affecting the prognosis of tracheotomy, such as the severity of the disease, treatment.In addition, most of the patients in these studies were specialized ICU patients.Therefore, more high-quality and large sample RCTs involving comprehensive ICU patients are needed for further confirmation in order to obtain more reliable evidence-based medical evidence.